Exam 1 - PK/PD Flashcards
How many receptors need to bound to acheive the greatest effect?
Example?
- All receptors bound
- Paralytics (we want total paralysis, not partial)
What are the 3 ways that drugs bond to receptors?
What type bonding is irreversible?
- Ionic, Hydrogen, Van der waals
- Covalent
Differentiate competitive vs non-competitive antagonism?
- Competitive: giving more agonist will overcome antagonistic effects
- Non-competitive: no amount of agonist will overcome antagonistic effects (insurmountable)
What is a partial and inverse agonist?
Examples of inverse agonists?
- Partial: has less effect than full agonist even in higher doses
- Inverse: binds at active site but causes an opposing effect from the agonist (propanolol, metoprolol, cetirizine, loratidine, prazosin, naloxone)
Upregulation vs downregulation?
Upregulation: receptors increase in number due to low level of ligand (more sensitive)
Downregulation: receptors decrease in number due to high levels of ligand (less sensitive)
What is tachyphylaxis?
What 2 drugs undergo this?
What condition?
Tachyphylaxis: Rapid tolerance to a drug produce diminishing effects with each administration
- Albuterol (receptors downregulate due to repetition)
- Ephedrine (depletion of stored presynaptic catecholamines with each dose)
- Pheochromocytoma (decreased β receptors in response to catecholamines)
What drugs bind to intracellular receptors?
- Insulin
- Steroids
- Milrinone
What drug class binds to circulating proteins?
Anticoagulants (Warfarin)
What is the vessel rich group?
Bolused drugs first distrubute to tissues that receive the bulk of arterial blood flow: the brain, heart, kidneys, and liver.
What is meant by a high and low VD?
High: drug distributes out of blood to tissue quickly - (lipid soluble drugs)
Low: drug stays within the cardiovascular system - (water soluble drugs)
What proteins do acidic and basic drugs bind to?
Acidic = Albumin
Basic = ⍺1-acid glycoprotein
Why do we care if drugs are bound or not?
- Protein bound drugs are not available to interact with their receptors
- Only unbound drugs can cross cell membranes
What factors/conditions can decrease plasma protein concentrations?
- Age
- Liver dx
- Renal failure
- Pregnancy
- Burns
- Acidosis
- Malnutrition
If a drugs normal free fraction is 2% and their albumin is dropped by half, what is the new free fraction?
What does this mean?
- 4%
- This means with the same dose, the patient may have double the effect which usually comes with undesirable effects
What drugs have a high VD?
Why?
- Thiopental, diazepam, propofol
- They are poorly protein bound and lipophilic
What drug has a low VD?
Why?
- Warfarin
- It is highly protein bound
What are the Phase I reactions?
What is their purpose?
- Oxidation, Reduction, and Hydrolysis
- Increases drug polarity to make them more water soluble in preparation for elimination
What is the phase II reaction?
What does it do?
- Conjugation
- Links covalently with a polar molecule to become more water soluble
What does it mean when CYP enzymes have more letters/number?
What is the most common CYP enzyme for anesthetic drugs?
- The enzyme group is more specific
- CYP3A4
Describe enzyme induction and inhibition?
Examples?
Induction - increases activity of enzyme → increases drug metabolism → decreases drug effects (phenobarbital)
Inhibition - decreases activity of enzyme → decreases drug metabolism → increases drug effects (grapefruit juice)
Hepatic clearence is ⎽ for most anesthetic drugs?
Constant
What is flow limited clearance?
- Rate of clearance is proportional to drug concentration
- More hepatic flow = more clearance
What is capacity limited clearance?
- Liver metabolism is the limiting factor for drug clearance
- Only a certain amount can be cleared, regardless of changes in flow
Describe the 3 processes that govern renal clearance?
- Filtration: glomerulus → tubule
- Secretion: PT capillaries → tubule (active transport)
- Reabsorption: tubule → PT capillaries (increased for lipid soluble drugs)
If a drug has a 1/2 time of 10 minutes, what fraction of drug remains after 40 mins?
1/16 th
Why do we need to be concerned about drug half time?
It affects dosing time. If redosed too soon, we can overdose a patient.
Ex: 100mcg of drug bolused with 1/2 time of 10 minutes.
- After 20 mins plasma conc. = 25 mcg
If redosed at 20 mins with another 100 mcg, the plasma dose would be 125 mcg.
What is context-sensitive half time?
Why does this matter?
- The half time after a continuous infusion (assuming constant concentration)
- Because many anesthetic drugs are lipid solubule and will accumulate in the tissues, meaning the longer the infusion is run, the longer the effects are seen.
What does pK mean?
Why does it matter?
- pK is the pH at which there will a 50/50 mixture of ionized and unionized drug
- Non-ionized drugs cross barriers better and are pharmacologically active
When do acids and bases become ionized?
- Acids become ionized in alkaline pH
- Bases become ionized in acidic pH
What are some drugs we give that are weak acids and weak bases?
Weak acids: barbituates
Weak bases: local anesthetics and opiods
What is the pneumonic to remember if a drug is ionized or not?
What number are nonionized drugs?
- Weak Acids: pK After pH (pH - pK)
- Weak Bases: pK Before pH (pK - pH)
- Negative numbers: “nicely negative numbers are nonionized”
What is ion trapping?
When a non-ionized drug becomes ionized in a part of the body and accumulates.
Ex: Mother with normal pH and baby with acidic pH → local anesthetic/opiod becomes ionized in baby’s body → ionized drug can’t cross membranes and accumulates, causing a increased effect on the baby
Why won’t a nerve block work well on ischemic tissues?
Because ischemic tissues are acidodic and will cause the LA (weak base) to become very ionized in those tissues, rendering them ineffective.
Differentiate potency and efficacy?
Potency: dose of the drug required to produce response (less drug = more potent)
Efficacy: the ability of a drug to produce a clinical effect
What is relative potency?
Why does it matter?
- The time to drug effect
- The lag time between drug administration (plasma concentration) and effect
- Important to understand drug onset and offset
How do you calculate therapeutic index?
LD50 ÷ ED50
How do you name enatiomers the rotate light right and left?
Right: Dextrorotatory
Left: Levorotatory
How do you name the molecule sequence of enatiomers?
R: Rectus (right/clockwise)
S: Sinister (left/counterclockwise)
What are the properties of racemic mixtures?
- Contain 50/50 mixture of enatiomers
- Optically inactive
- One is active and one is inactive or causes side effects
What is the enatiomer of albuterol?
Xopenex
What is the enatiomer of cisatracurium?
Atracurium
What is the more potent isomer of ketamine?
S-ketamine
